A Biweekly GLP-1R Agonist Designed With Drug-Free Intervals for Enhanced Efficacy, Receptor Homeostasis and Gastrointestinal Tolerability.

AIM: To develop a next-generation, longer-acting, more-clinical-benefits agonist to achieve sustained efficacy with improved tolerability. METHODS: CT130 was designed from semaglutide. Binding affinity was validated via molecular dynamics and cellular assays. Pharmacokinetics were profiled in SD rats; metabolic efficacy was evaluated in B6/ob and DIO mice (CT130 biweekly vs semaglutide weekly). Receptor trafficking dynamics and cholesterol regulation were dissected mechanistically. Toxicology was assessed in rodents and a primate pilot study. RESULTS: CT130 retained high GLP‑1R affinity (EC50 = 21 pM) and exhibited a prolonged half‑life (13.9 h, 1.4‑fold vs semaglutide). Biweekly CT130 outperformed weekly semaglutide in body weight reduction, glucose tolerance, TC, LDL‑C, body fat percentage and other metabolic indicators. Drug‑free intervals enabled near‑complete GLP‑1R recycling, termed "GLP‑1R recovery", preserving receptor homeostasis, whereas semaglutide drove progressive internalization. CT130 also alleviated constipation risk (increased fecal water) and uniquely lowered cholesterol by suppressing SREBP‑2, which upregulated LDLR while decoupling from PCSK9 induction, thereby promoting fecal cholesterol excretion without altering bile acid flux. No pathological changes were observed even at tens to 200 times the semaglutide dose. In monkeys, two biweekly doses induced > 10% weight loss with good safety. CONCLUSIONS: CT130 is a safe, once biweekly preclinical candidate that incorporates drug free intervals to allow GLP 1R restore. It delivers robust, lasting metabolic benefits with improved gastrointestinal tolerability, and offering a template for next generation long acting GLP 1R agonists.